Proliferation occurs by the development of cells through the cell cycle characterized by the division of one cell into two cells. The cell cycle consists of 5 phases: G0 phase, G1 phase, S phase, G2 phase, and M phase. During the G0 phase, cells are quiescent and most cells in the body are in this phase. During the G1 phase, cells respond to signals to divide, and produce RNA and proteins necessary for DNA synthesis. During the S phase (SE, early S-phase; SM, middle S-phase; and SL, late S-phase), cells replicate their DNA. During the G2 phase, cells continue to grow and protein synthesis occurs in preparation for mitosis. During the mitotic (M) phase, a single cell divides into two daughter cells. Cells of aberrant proliferation, such as a case of cancer, are generated by alterations in the cell cycle described above, and the alterations may result from over-expression of genes, mutation of regulatory genes, or defects in DNA damage checkpoints.
There are many types of diseases related to the cells of aberrant proliferation, and representative diseases may occur due to carcinogenesis, cancer, bacterial infection, immunological rejection of transplanted organs, viral infection, autoimmune disease (for example, arthritis, lupus, inflammatory bowel disease, Sjogren's syndrome, multiple sclerosis, and the like), or combinations thereof. The most widely known, representative disease related to the cells of aberrant proliferation is cancer.
In general, cancer broadly refers to various diseases characterized by proliferation of disease cells caused by abnormal cell division. The characteristics that are consistent with all the known types of cancer include abnormal occurrence in genetic materials of cancer cells and descendant cells of the cancer cells. When cells become cancerous, the cells proliferate regardless of normal limitation, and invade and destroy adjacent tissues. In addition, through a process called metastasis, the cells may spread to an anatomical distal region.
Meanwhile, about 2,000 cases related to clinical trials of gene therapy have been permitted and carried out over the past 25 years. However, in recent years, in contrast to what has been reported as successful gene therapy for genetic disorders caused by some single-gene deletions, gene therapy for cancer is not successfully done as much as expected, regardless of the greatest number of data related to clinical trials of gene therapy in cancer fields. In addition, the anti-cancer gene therapy using an oncolytic adenovirus vector, which had great expectations some years ago, now only shows limited therapeutic effects in some types of head and neck cancer.
A common awareness regarding the cause of such a low gene therapy effect for cancer is that it is urgent to develop a vector that is capable of delivering therapeutic genes in an efficient manner to cancerous tissues. Actually, according to the clinical trials of cancer gene therapy in the past, the gene delivery efficiency with respect to cancer cells is found to be less than 1% of cancer cells with respect to the entire cancerous tissues. In order to improve such inefficient gene delivery with respect to the cancerous tissues, various types of oncolytic viruses had been developed and studied. However, due to inflammation induced by immunogenicity, rapid viral clearance, difficulties in developing a virus having a complicated gene structures, and transformation and inactivation of viruses in the body, it fails to obtain expected effects.
However, starting with the recent cancer gene therapy using an oncolytic vaccinia virus and showing highly desired clinical trial results as compared with the past clinical trial results, cancer gene therapy using a replication-competent retrovirus (RCR) has been approved in the United States in 2010. Accordingly, it is currently in a situation that a phase 1 clinical trial has been completed in 2011 and a phase 2 clinical trial is being studied. In this regard, studies for developing practical use and clinical trials of the vector system are expected to increase in the future.